Viruses can be targeted for entry and replication in cancer cells and armed to amplify the effects of conventional chemo- or radiation therapy. In particular, since lymphoma remissions were documented after acute measles, reprogrammed measles viruses (MV) appear ideal to treat lymphoma patients failing to respond to conventional therapies. We have already proven the oncolytic efficacy of vaccine-lineage MV in lymphoma xenograft models, and have shown that receptor-targeting and prodrug convertase-arming enhances specificity and efficacy of virotherapy. Tumor regressions, however, were temporary. We now plan to assess the efficacy of alternative modalities of targeting and arming. As to cell-entry targeting, we will compare the infection efficacy of MV with different receptor specificity in clinical materials from lymphoma patients including tumor tissue and circulating cells. As to post-entry targeting, we will generate MV with the potential of preferential replication through specific defects in their innate immunity control proteins. We will arm MV by expression of the natrium-iodine symporter (NIS) protein, allowing concentration of 131I. The efficacy of these viruses will be compared with that of viruses expressing the prodrug convertase purine nucleotide phosphorylase (PNP), activating the lymphoma chemotherapeutic fludarabine phosphate (F-araAMP). To shield vectors from MV-neutralizing antibodies, we will cover the MV ribonucleocapsid with the structurally related but non-cross-reactive envelopes of other paramyxoviruses. We will test the efficacy of reprogrammed viruses in infecting cells of lymphoma patients, and in reducing xenografts of different lymphoma types, including mantle cell lymphoma. We will test the oncolytic efficacy of sequential application of viruses with alternative envelopes in immunocompetent mice with implanted congenic tumor allografts. PUBLIC HEALTH RELEVANCE: This grant application foresees to reprogram a human virus that is naturally lymphotropic into a lymphoma therapeutic. We will develop complementary avenues of experimentation to reprogram measles virus: adding different layers of cancer cell specificity (targeting), enhancing potency (arming), and shielding the virus turned into a therapeutic vector from the host immune system.